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Myricetin induces apoptosis in the adenomatous polyps. A. (Left) TUNEL stained adenomatous cells in small intestinal and colonic polyps in vehicle control and myricetin-treated mice (400×). (Right) TUNEL stained DAB-positive cells (with brown staining) were counted in five arbitrarily selected fields. Bars represent means ± S.D. of six mice. **, p < 0.01 vs. vehicle control. B. Western blot analysis of the expression of apoptotic proteins in small intestinal and colonic adenomatous polyps. Experiments were performed in triplicate. **, p < 0.01 vs. vehicle control.
Source publication
Myricetin is a natural dietary flavonoid compound. We evaluated the efficacy of myricetin against intestinal tumorigenesis in adenomatous polyposis coli multiple intestinal neoplasia (APCMin/+) mice. Myricetin was given orally once a day for 12 consecutive weeks. APCMin/+ mice fed with myricetin developed fewer and smaller polyps without any advers...
Citations
... Result revealed that both IL-1β precursor as well as mature IL-1β were strongly prevented in small intestinal and colonic polyps. Furthermore, it demonstrated that myricetin decrease the levels of TNF-α by 89.4% and 91.9%, IL-6 by 76.6% and 89.2% and MCP-1 by 77.2% and 83.3% in small intestinal and colonic polyps, correspondingly [52]. Inflammatory cytokine secretions were meaningfully inhibited by myricetin pretreatment. ...
Cancer is a major public health concern worldwide and main burden of the healthcare system. Regrettably, most of the currently used cancer treatment approaches such as targeted therapy, chemotherapy, radiotherapy and surgery usually cause adverse complications including hair loss, bone density loss, vomiting, anemia and other complications. However, to overcome these limitations, there is an urgent need to search for the alternative anticancer drugs with better efficacy as well as less adverse complications. Based on the scientific evidences, it is proven that naturally occurring antioxidants present in medicinal plants or their bioactive compounds might constitute a good therapeutic approach in diseases management including cancer. In this regard, myricetin, a polyhydroxy flavonol found in a several types of plants and its role in diseases management as anti-oxidant, anti-inflammatory and hepato-protective has been documented. Moreover, its role in cancer prevention has been noticed through modulation of angiogenesis, inflammation, cell cycle arrest and induction of apoptosis. Furthermore, myricetin plays a significant role in cancer prevention through the inhibition of inflammatory markers such as inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (Cox-2). Moreover, myricetin increases the chemotherapeutic potential of other anticancer drugs through modulation of cell signaling molecules activity. This review elaborates the information of myricetin role in cancer management through modulating of various cell-signaling molecules based on in vivo and in vitro studies. In addition, synergistic effect with currently used anticancer drugs and approaches to improve bioavailability are described. The evidences collected in this review will help different researchers to comprehend the information about its safety aspects, effective dose for different cancers and implication in clinical trials. Moreover, different challenges need to be focused on engineering different nanoformulations of myricetin to overcome the poor bioavailability, loading capacity, targeted delivery and premature release of this compound. Furthermore, some more derivatives of myricetin need to be synthesized to check their anticancer potential.
... Myricetin reduces the concentration of IL-6 and PGE2 in the blood. These results suggested that the mechanism of myricetin in treating adenoma may be the downregulation of phosphorylated p38MAPK/Akt/mTOR signaling pathway (55). Another study showed that myricetin significantly reduces the size and degree of small CRAs in AOM/DSS mice. ...
Colorectal adenoma (CRA) is a premalignant lesion of colorectal cancer. The current treatment is surgical resection, but CRA is prone to recurrence, and there is no safe and effective drug to prevent adenoma recurrence and canceration. Recent studies have shown that natural compounds in plants have favorable antitumor effects. According to preclinical studies, natural polyphenols can regulate different signal pathways and targets to play a role in the treatment of CRA, which is closely related to its inhibition of proliferation, induction of apoptosis, inhibition of inflammation and oxidative stress, and regulation of intestinal flora. Natural polyphenols are potential candidates for CRA therapy due to their remarkable efficacy and safety. In the present review, attention was paid to the experimental research progress of natural polyphenols extracted from numerous plants in the treatment of CRA in the last 10 years. The present review provided new guidance for the study of CRA, clarified the therapeutic role of polyphenols in CRA, and evaluated for the first time, to the best of our knowledge, the therapeutic potential of natural polyphenols to treat CRA by targeting multiple genes and signal pathways and epigenetic modification.
... Li et al. [258] assessed the effectiveness of myricetin against intestinal tumorigenesis in adenomatous polyposis coli multiple intestinal neoplasia (APC Min/+ ) mice. Promoting apoptosis in adenomatous polyps, myricetin-fed APC Min/+ mice grew fewer, smaller polyps and did not appear to experience negative side effects. ...
... Promoting apoptosis in adenomatous polyps, myricetin-fed APC Min/+ mice grew fewer, smaller polyps and did not appear to experience negative side effects. By modifying the GSK-3 and Wnt/catenin pathways, lowering the levels of the proinflammatory cytokines IL-6 and PGE2, and downregulating the phosphorylated p38 MAPK/Akt/mTOR signaling pathway, myricetin prevents the growth of intestinal tumors [258]. ...
Simple Summary
Colorectal cancer (CRC) is a significant cause of death worldwide. The inefficacy of the current treatment regimens is reflected in the frequent recurrence and emergence of a drug-resistant form of CRC. Numerous published reports from independent investigators around the globe have shown the great potential of natural products as a source of anti-CRC drug-leads with novel functions. Here, we have reviewed the literature on phenolic phytochemicals carrying anti-CRC activity in various in vivo models and analyzed their molecular basis of action to understand the implications of these findings in the future treatment and prevention of CRC.
Abstract
Colorectal cancer (CRC) is the third most diagnosed and second leading cause of cancer-related death worldwide. Limitations with existing treatment regimens have demanded the search for better treatment options. Different phytochemicals with promising anti-CRC activities have been reported, with the molecular mechanism of actions still emerging. This review aims to summarize recent progress on the study of natural phenolic compounds in ameliorating CRC using in vivo models. This review followed the guidelines of the Preferred Reporting Items for Systematic Reporting and Meta-Analysis. Information on the relevant topic was gathered by searching the PubMed, Scopus, ScienceDirect, and Web of Science databases using keywords, such as “colorectal cancer” AND “phenolic compounds”, “colorectal cancer” AND “polyphenol”, “colorectal cancer” AND “phenolic acids”, “colorectal cancer” AND “flavonoids”, “colorectal cancer” AND “stilbene”, and “colorectal cancer” AND “lignan” from the reputed peer-reviewed journals published over the last 20 years. Publications that incorporated in vivo experimental designs and produced statistically significant results were considered for this review. Many of these polyphenols demonstrate anti-CRC activities by inhibiting key cellular factors. This inhibition has been demonstrated by antiapoptotic effects, antiproliferative effects, or by upregulating factors responsible for cell cycle arrest or cell death in various in vivo CRC models. Numerous studies from independent laboratories have highlighted different plant phenolic compounds for their anti-CRC activities. While promising anti-CRC activity in many of these agents has created interest in this area, in-depth mechanistic and well-designed clinical studies are needed to support the therapeutic use of these compounds for the prevention and treatment of CRC.
... Myricetin has multiple biological activities, such as antioxidant, anti-diabetic, anti-inflammatory, anticarcinogenic and anti-proliferative effects [2][3][4][5][6][7][8][9][10][11][12][13][14][15]. In previous study, myricetin were also reported which could treat and prevent colitis and the risk of colitis-associated colorectal cancer (CAC) [16]. However, myricetin exhibits poor water-solubility and low stability in body when it was administrated orally. ...
Myricetin is a common plant-derived flavonoid and exhibits a wide range of activities. However, myricetin also exhibits substantial limitations, such as its poor water-solubility and low stability in body when it was administrated orally. To solve these problems, a series of myricetin derivatives with different disaccharide groups were designed, synthesized and evaluated their hypoglycemic activities. All synthesized compounds displayed significant α-glucosidase inhibitory activity in comparison with acarbose in vitro, which indicated that myricetin derivatives with different disaccharide groups had good hypoglycemic activity and could be further developed as hypoglycemic drugs.
... Death receptors (such as TRAIL-DR4 and -DR5, TNF-TNFR1, and Fas-FasL) that are bound by ligands primarily activate the extrinsic apoptosis pathway. When such death ligands are stimulated, caspase-8 is recruited, and then caspase-3/6/7 is activated [55]. ...
Breast cancer is still a severe origin of malignant demise in females, and its prevalence is rising worldwide. Triple-negative breast cancer (TNBC) is a diversified aggressive breast tumor distinguished by inadequate prognosis, early recurrence, high invasion, and extremely metastasized disease. Chemotherapy is being used to treat it; however, it has low efficacy. On the other hand, with the growing number of corroborations on subtypes of TNBC and molecular biology of tumors, significant advancement in TNBC targeted treatment has been made. Myricetin (MYR), a polyhydroxyflavonol compound widely found in nature, has been shown to possess anticancer effects in various cancers. Though, the mechanisms and impacts of MYR on metastasis of TNBC remain unclear. Early and late apoptotic cell death and cell proliferation inhibition were observed in MYR-treated TNBC cells. MYR modulated cell cycle, pro-angiogenic, and invasion effects via the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/Protein kinase B (PKB/also known as AKT) signaling pathways. Moreover, it regulates the expression of MAPK, PI3K/AKT/mTOR, IκB/NF-κB, Hippo, STAT3, GSK-3β, Nrf2/HO-1, TLR, eNOS / NO, ACE, and AChE. Here, we review the anticancer effects of MYR for TNBC and target the PI3K/AKT/mTOR pathway as a therapeutic target for the fruitful treatment of TNBC to summarize MYR's therapeutic potential.
... Myricetin can be found in many edible plants, such as medicinal herbs, teas, and many fruits, possessing antioxidative, anticarcinogenic, and anti-inflammatory properties [123][124][125]. Myricetin has been proven to improve the intestinal barrier-promoting efficiency in rat IEC-6 cells evidenced by enhanced transepithelial electrical resistance and anti-bacterial effect [126]. ...
TLR4/NF-κB is a key inflammatory signaling transduction pathway, closely involved in cell differentiation, proliferation, apoptosis, and pro-inflammatory response. Toll like receptor 4 (TLR4), the first mammalian TLR to be characterized, is the innate immune receptor that plays a key role in inflammatory signal transductions. Nuclear factor kappa B (NF-κB), the TLR4 downstream, is the key to accounting for the expression of multiple genes involved in inflammatory responses, such as pro-inflammatory cytokines. Inflammatory bowel disease (IBD) in humans is a chronic inflammatory disease with high incidence and prevalence worldwide. Targeting the TLR4/NF-κB signaling pathway might be an effective strategy to alleviate intestinal inflammation. Polyphenol phytochemicals have shown noticeable alleviative effects by acting on the TLR4/NF-κB signaling pathway in intestinal inflammation. This review summarizes the pharmacological effects of more than 20 kinds of polyphenols on intestinal inflammation via targeting the TLR4/NF-κB signaling pathway. We expected that polyphenol phytochemicals targeting the TLR4/NF-κB signaling pathway might be an effective approach to treat IBD in future clinical research applications.
... A deeper analysis has revealed that the treated mice presented an increase of active non-phosphorylated glycogen synthase kinase 3 beta (GSK-3β) and an increase of the destabilized form of phosphorylated β-catenin (Ser37) levels, indicating that myricetin, through GSK-3β, inhibited β-catenin activation, probably inhibited both expression and phosphorylation of c-Jun N-terminal kinase (JNK), p38/MAPK, ERK1, as well as AKT and mTOR phosphorylation. Moreover, a decrease of inflammation was also observed [71], and the same result was obtained by another study conducted using a more severe mouse model of colonic colitis. It was found that myricetin (100 mg/kg) administration decreased cytokines production, and expression of NF-κB and COX-2. ...
Natural compounds have always represented valuable allies in the battle against several illnesses, particularly cancer. In this field, flavonoids are known to modulate a wide panel of mechanisms involved in tumorigenesis, thus rendering them worthy candidates for both cancer prevention and treatment. In particular, it was reported that flavonoids regulate apoptosis, as well as hamper migration and proliferation, crucial events for the progression of cancer. In this review, we collect recent evidence concerning the anti-cancer properties of the flavonols myricetin and kaempferol, discussing their mechanisms of action to give a thorough overview of their noteworthy capabilities, which are comparable to those of their most famous analogue, namely quercetin. On the whole, these flavonols possess great potential, and hence further study is highly advised to allow a proper definition of their pharmaco-toxicological profile and assess their potential use in protocols of chemoprevention and adjuvant therapies.
... Besides, MY attenuated the inhibitory effect of IFN-γ to T cells in the co-culture system. Importantly, despite the poor bioavailability, MY treatment could suppress the tumorigenesis of spontaneous colorectal cancer and reduce breast cancer metastasis in immune-competent mice [29,[59][60][61]. These results suggested that compared with the direct killing of tumor cells by high concentration, down-regulation of the immune checkpoint expression is more likely to be the vital mechanism for the anti-tumor effect of MY in vivo. ...
Programmed death ligand-1 (PD-L1) and indoleamine 2, 3-dioxygenase 1 (IDO1) are immune checkpoints induced by interferon-γ (IFN-γ) in the tumor microenvironment, leading to immune escape of tumors. Myricetin (MY) is a flavonoid distributed in many edible and medicinal plants. In this study, MY was identified to inhibit IFN-γ-induced PD-L1 expression in human lung cancer cells. It also reduced the expression of IDO1 and the production of kynurenine which is the product catalyzed by IDO1, while didn’t show obvious effect on the expression of major histocompatibility complex-I (MHC-I), a crucial molecule for antigen presentation. In addition, the function of T cells was evaluated using a co-culture system consist of lung cancer cells and the Jurkat-PD-1 T cell line overexpressing PD-1. MY restored the survival, proliferation, CD69 expression and interleukin-2 (IL-2) secretion of Jurkat-PD-1 T cells suppressed by IFN-γ-treated lung cancer cells. Mechanistically, IFN-γ up-regulated PD-L1 and IDO1 at the transcriptional level through the JAK-STAT-IRF1 axis, which was targeted and inhibited by MY. Together, our research revealed a new mechanism of MY mediated anti-tumor activity and highlighted the potential implications of MY in tumor immunotherapy.
... In line with the proapoptotic effect exhibited by myricetin on many tumor cell lines [62,[68][69][70][71][72][73][74][75][76][77], this compound has also induced apoptosis in endothelial cells through a reactive oxygen species (ROS)-dependent mechanism [67]. Despite the fact that in vivo studies in rodents support the chemopreventive role of myricetin in different cancer models [78][79][80][81][82][83][84][85], there is no current clinical evidence of its preventive activity in cancer, nor are there any active clinical trials using this compound. Additional in vitro studies suggest a synergistic effect of myricetin with traditional anticancer drugs [86]. ...
Despite the extensive knowledge on cancer nature acquired over the last years, the high incidence of this disease evidences a need for new approaches that complement the clinical intervention of tumors. Interestingly, many types of cancer are closely related to dietary habits associated with the Western lifestyle, such as low fruit and vegetable intake. Recent advances around the old-conceived term of chemoprevention highlight the important role of phytochemicals as good candidates for the prevention or treatment of cancer. The potential to inhibit angiogenesis exhibited by many natural compounds constituent of plant foods makes them especially interesting for their use as chemopreventive agents. Here, we review the antitumoral potential, with a focus on the antiangiogenic effects, of phenolic and polyphenolic compounds, such as quercetin or myricetin; terpenoids, such as ursolic acid or kahweol; and anthraquinones from Aloe vera, in different in vitro and in vivo assays, and the available clinical data. Although clinical trials have failed to assess the preventive role of many of these compounds, encouraging preclinical data support the efficacy of phytochemicals constituent of diet in the prevention and treatment of cancer, but a deeper understanding of their mechanisms of action and better designed clinical trials are urgently needed.
... Myricetin inhibits the Wnt/β-catenin pathway by modulating GSK3 activity and reduces cytoplasmic and nuclear β-catenin levels in vivo with 100 mg/kg. In addition, myricetin inhibits the proliferation of intestinal polyps in APC Min/+ mice by modulating the localization of β-catenin in intestinal adenomatous cells and negatively regulates the expression of PCNA and the Wnt-target gene cyclin D1, reducing the number of intestinal polyps, besides promoting apoptosis by regulating pro-apoptotic proteins and inflammatory cytokines [108]. ...
Simple Summary
Colorectal cancer (CRC) is an emerging public health problem and the second leading cause of death worldwide, with a significant socioeconomic impact in several countries. The 5-year survival rate is only 12% due to the lack of early diagnosis and resistance to available treatments, and the canonical Wnt signaling pathway is involved in this process. This review underlines the importance of understanding the fundamental roles of this pathway in physiological and pathological contexts and analyzes the use of naturally occurring small molecules that inhibits the Wnt/β-catenin pathway in experimental models of CRC. We also discuss the progress and challenges of moving these small molecules off the laboratory bench into the clinical platform.
Abstract
Colorectal cancer (CRC) ranks second in the number of cancer deaths worldwide, mainly due to late diagnoses, which restrict treatment in the potentially curable stages and decrease patient survival. The treatment of CRC involves surgery to remove the tumor tissue, in addition to radiotherapy and systemic chemotherapy sessions. However, almost half of patients are resistant to these treatments, especially in metastatic cases, where the 5-year survival rate is only 12%. This factor may be related to the intratumoral heterogeneity, tumor microenvironment (TME), and the presence of cancer stem cells (CSCs), which is impossible to resolve with the standard approaches currently available in clinical practice. CSCs are APC-deficient, and the search for alternative therapeutic agents such as small molecules from natural sources is a promising strategy, as these substances have several antitumor properties. Many of those interfere with the regulation of signaling pathways at the central core of CRC development, such as the Wnt/β-catenin, which plays a crucial role in the cell proliferation and stemness in the tumor. This review will discuss the use of naturally occurring small molecules inhibiting the Wnt/β-catenin pathway in experimental CRC models over the past decade, highlighting the molecular targets in the Wnt/β-catenin pathway and the mechanisms through which these molecules perform their antitumor activities.
